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Methods and devices for inducing collapse in lung regions fed by
collateral pathways

Abstract

Disclosed are methods and devices for treating a patient's lung region. A
catheter is deployed into the lung. The catheter is used to apply heat to
a targeted lung region wherein the heat affects fluid flow within the
targeted lung region.

1. A method of treating a patient's lung region, comprising: deploying a
catheter into a lung; using the catheter to apply heat to a targeted lung
region wherein the heat affects fluid flow within the targeted lung
region.

2. A method as in claim 1, wherein the heat reduces or terminates fluid
flow within the targeted lung region.

3. A method as in claim 1, wherein the heat generates a reaction in tissue
of the targeted lung region that results in a reduction or prevention of
fluid flow within the targeted lung region.

4. A method as in claim 1, wherein the heat seals portions of the lung
together.

5. A method as in claim 1, wherein the heat scleroses lung tissue within
the targeted lung region

6. A method as in claim 1, wherein the heat promotes fibrosis in or around
the targeted lung region

7. A method as in claim 1, wherein the heat creates an inflammatory
response in the targeted lung region.

8. A method as in claim 1, wherein the heat affects fluid flow by reducing
or preventing collateral fluid flow into the targeted lung region.

9. A method as in claim 1, wherein deploying a catheter into a lung
comprises deploying a catheter through a bronchial tree into the targeted
lung region such that a distal end of the catheter is positioned near the
targeted lung region.

10. A method as in claim 9, wherein the heat is applied via the distal end
of the delivery catheter.

Description

REFERENCE TO PRIORITY DOCUMENTS

[0001] This application is a continuation of co-pending U.S. patent
application Ser. No. 10/384,899 entitled "Methods and Devices for
Inducing Collapse in Lung Regions Fed by Collateral Pathways", filed Mar.
6, 2003, which claims priority of U.S. Provisional Patent Application
Ser. No. 60/363,328 entitled "Methods and Devices for Inducing Collapse
in Lung Regions Fed by Collateral Pathways", filed Mar. 8, 2002. Priority
of the aforementioned filing dates is hereby claimed, and the disclosures
of the aforementioned patent application are hereby incorporated by
reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates generally to methods and devices for use in
performing pulmonary procedures and, more particularly, to procedures for
treating various diseases of the lung.

[0004] 2. Description of the Related Art

[0005] Pulmonary diseases such as chronic obstructive pulmonary disease
(COPD) reduce the ability of one or both lungs to fully expel air during
the exhalation phase of the breathing cycle. The term "Chronic
Obstructive Pulmonary Disease" (COPD) refers to a group of diseases that
share a major symptom, dyspnea. Such diseases are accompanied by chronic
or recurrent obstruction to air flow within the lung. Because of the
increase in environmental pollutants, cigarette smoking, and other
noxious exposures, the incidence of COPD has increased dramatically in
the last few decades and now ranks as a major cause of
activity-restricting or bed-confining disability in the United States.
COPD can include such disorders as chronic bronchitis, bronchiectasis,
asthma, and emphysema. While each has distinct anatomic and clinical
considerations, many patients may have overlapping characteristics of
damage at both the acinar (as seen in emphysema) and the bronchial (as
seen in bronchitis) levels, almost certainly because one pathogenic
mechanism--cigarette smoking is common to both. (Robbins eds.,
Pathological Basis of Disease, 5.sup.th edition, pg 683)

[0006] Emphysema is a condition of the lung characterized by the abnormal
permanent enlargement of the airspaces distal to the terminal bronchiole,
accompanied by the destruction of their walls, and without obvious
fibrosis. It is known that emphysema and other pulmonary diseases reduce
the ability of one or both lungs to fully expel air during the exhalation
phase of the breathing cycle. One of the effects of such diseases is that
the diseased lung tissue is less elastic than healthy lung tissue, which
is one factor that prevents full exhalation of air. During breathing, the
diseased portion of the lung does not fully recoil due to the diseased
(e.g., emphysematic) lung tissue being less elastic than healthy tissue.
Consequently, the diseased lung tissue exerts a relatively low driving
force, which results in the diseased lung expelling less air volume than
a healthy lung. The reduced air volume exerts less force on the airway,
which allows the airway to close before all air has been expelled,
another factor that prevents full exhalation.

[0007] The problem is further compounded by the diseased, less elastic
tissue that surrounds the very narrow airways that lead to the alveoli
(the air sacs where oxygen-carbon dioxide exchange occurs). This tissue
has less tone than healthy tissue and is typically unable to maintain the
narrow airways open until the end of the exhalation cycle. This traps air
in the lungs and exacerbates the already-inefficient breathing cycle. The
trapped air causes the tissue to become hyper-expanded and no longer able
to effect efficient oxygen-carbon dioxide exchange. One way of deflating
the diseased portion of the lung is to applying suction to these narrow
airways. However, such suction may undesirably collapse the airways,
especially the more proximal airways, due to the surrounding diseased
tissue, thereby preventing successful fluid removal.

[0008] In addition, hyper-expanded lung tissue occupies more of the
pleural space than healthy lung tissue. In most cases, a portion of the
lung is diseased while the remaining part is relatively healthy and
therefore still able to efficiently carry out oxygen exchange. By taking
up more of the pleural space, the hyper-expanded lung tissue reduces the
amount of space available to accommodate the healthy, functioning lung
tissue. As a result, the hyper-expanded lung tissue causes inefficient
breathing due to its own reduced functionality and because it adversely
affects the functionality of adjacent, healthier tissue.

[0009] Lung volume reduction surgery is a conventional method of treating
lung diseases such as emphysema. According to the lung reduction
procedure, a diseased portion of the lung is surgically removed, which
makes more of the pleural space available to accommodate the functioning,
healthier portions of the lung. The lung is typically accessed through a
median sternotomy or lateral thoracotomy. A portion of the lung,
typically the upper lobe of each lung, is freed from the chest wall and
then resected, e.g., by a stapler lined with bovine pericardium to
reinforce the lung tissue adjacent the cut line and also to prevent air
or blood leakage. The chest is then closed and tubes are inserted to
remove fluid from the pleural cavity. The conventional surgical approach
is relatively traumatic and invasive, and, like most surgical procedures,
is not a viable option for all patients.

[0010] Some recently proposed treatments include the use of devices that
isolate a diseased region of the lung in order to reduce the volume of
the diseased region, such as by collapsing the diseased lung region.
According to such treatments, isolation devices are implanted in airways
feeding the targeted region of the lung to isolate the region of the lung
targeted for volume reduction or collapse. These implanted isolation
devices can be, for example, one-way valves that allow flow in the
exhalation direction only, occluders or plugs that prevent flow in either
direction, or two-way valves that control flow in both directions.
However, even with the implanted isolation devices properly deployed, air
can flow into the isolated lung region via a collateral pathway. This can
result in the diseased region of the lung still receiving air even though
the isolation devices were implanted into the direct pathways to the
lung. Collateral flow can be, for example, air flow that flows between
segments of a lung, or it can be, for example, air flow that flows
between lobes of a lung, as described in more detail below.

[0011] Collateral flow into an isolated lung region can make it difficult
to achieve a desired flow dynamic for the lung region. Moreover, it has
been shown that as the disease progresses, the collateral flow throughout
the lung can increase, which makes it even more difficult to properly
isolate a diseased lung region by simply implanting flow control valves
in the bronchial passageways that directly feed air to the diseased lung
region.

[0012] In view of the foregoing, there is a need for a method and device
for regulating fluid flow to and from a region of a lung that is supplied
air through a collateral pathway, such as to achieve a desired flow
dynamic or to induce collapse in the lung region.

SUMMARY

[0013] Disclosed are methods and devices for regulating fluid flow to and
from a lung region that is supplied air through one or more collateral
pathways, such as to induce collapse in the lung region or to achieve a
desired flow dynamic. In accordance with one aspect of the invention,
there is disclosed a method of regulating fluid flow for a targeted lung
region, comprising identifying at least one collateral pathway that
provides collateral fluid flow into the targeted lung region and
performing an intervention within the lung to reduce the amount of
collateral fluid flow provided to the targeted lung region through the
collateral pathway. The method can also include identifying at least one
direct pathway that provides direct fluid flow into the targeted lung
region and deploying a bronchial isolation device in the direct pathway
to regulate fluid flow to the targeted lung region through the direct
pathway.

[0014] Also disclosed is a method of regulating fluid flow for a targeted
lung region, comprising reducing direct fluid flow in a direct pathway
that provides direct fluid flow to the targeted lung region; and reducing
collateral fluid flow that flows through a collateral pathway to the
targeted lung region.

[0015] Also disclosed is a method of treating a patient's lung region,
comprising deploying a catheter into a lung; and using the catheter to
apply heat to a targeted lung region wherein the heat affects fluid flow
within the targeted lung region.

[0016] Other features and advantages of the present invention should be
apparent from the following description of various embodiments, which
illustrate, by way of example, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 illustrates an anterior view of a pair of human lungs and a
bronchial tree.

[0018] FIG. 2 illustrates a lateral view of the right lung.

[0019] FIG. 3 illustrates a lateral view of the left lung.

[0020] FIG. 4 illustrates an anterior view of the trachea and a portion of
the bronchial tree.

[0021] FIG. 5 illustrates an anterior view of a lung having a lung lobe
that is receiving collateral air flow through a collateral pathway
comprised of an incomplete interlobar fissure.

[0022] FIG. 6 illustrates an anterior view of a lung having a lung segment
that is receiving collateral air flow.

[0023] FIG. 7 illustrates the delivery of a flowable therapeutic agent to
a targeted lung region using a balloon-tipped delivery catheter.

[0024] FIG. 8 illustrates the delivery of a flowable therapeutic agent to
a targeted lung region using a delivery catheter.

[0032] FIG. 16 illustrates the percutaneous suction of a targeted lung
region using a suction catheter.

[0033] FIG. 17 illustrates the sealing of collateral flow paths between
the right upper lobe and the right middle lobe through the use of a
two-part adhesive.

[0034] FIG. 18 illustrates the use of shunt tubes that are mounted in
bronchial passageway to provide free air pathways to a targeted lung
region.

[0035] FIG. 19 is a cross-sectional view of a flow control element that
allows fluid flow in a first direction but blocks fluid flow in a second
direction.

[0036] FIG. 20 shows a perspective view of another embodiment of a flow
control element.

[0037] FIG. 21 shows a cross-sectional, perspective view of the flow
control element of FIG. 21.

[0038] FIG. 22 shows a valve element.

[0039] FIG. 23 shows a side view of the valve element of FIG. 22.

[0040] FIG. 24 shows a cross-sectional view of the valve element of FIG.
22 along the line 24-24 of FIG. 23.

[0041] FIG. 25 shows an enlarged, sectional view of the portion of the
flow control element contained within line 25 of FIG. 22.

DETAILED DESCRIPTION

[0042] Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as is commonly understood by one of skill in
the art to which the invention(s) belong.

[0043] Disclosed are methods and devices for regulating fluid flow to and
from a region of a patient's lung, such as to achieve a desired fluid
flow dynamic to a lung region during respiration and/or to induce
collapse in one or more lung regions that are supplied air through one or
more collateral pathways. An identified region of the lung (referred to
herein as the "targeted lung region") is targeted for flow regulation,
such as to achieve volume reduction or collapse. The targeted lung region
is then bronchially isolated to regulate fluid flow to the targeted lung
region through bronchial pathways that directly feed fluid to the
targeted lung region. If a desired flow characteristic to the targeted
region is not achieved, or if the targeted lung region does not collapse
after bronchially isolating the targeted lung region, then it is possible
that a collateral pathway is feeding air to the targeted lung region. The
collateral flow can prevent the targeted lung region from collapsing. In
such a case, the collateral pathway is identified and an intervention is
performed within the lung to modify or inhibit fluid flow into the
targeted lung region via the collateral pathway, such as according to the
methods described herein. While the invention can involve such treatment
of collateral flow pathways in combination with bronchial isolation, it
should be understood that the invention may also be practiced without
bronchial isolation in some circumstances. Further, the invention also
encompasses temporary bronchial isolation while treating lung regions fed
by collateral pathways.

Exemplary Lung Regions

[0044] Throughout this disclosure, reference is made to the term "lung
region". As used herein, the term "lung region" refers to a defined
division or portion of a lung. For purposes of example, lung regions are
described herein with reference to human lungs, wherein some exemplary
lung regions include lung lobes and lung segments. Thus, the term "lung
region" as used herein can refer, for example, to a lung lobe or a lung
segment. Such nomenclature conform to nomenclature for portions of the
lungs that are known to those skilled in the art. However, it should be
appreciated that the term lung region does not necessarily refer to a
lung lobe or a lung segment, but can refer to some other defined division
or portion of a human or non-human lung.

[0045] FIG. 1 shows an anterior view of a pair of human lungs 110, 115 and
a bronchial tree 120 that provides a fluid pathway into and out of the
lungs 110, 115 from a trachea 125, as will be known to those skilled in
the art. As used herein, the term "fluid" can refer to a gas, a liquid,
or a combination of gas(es) and liquid(s). For clarity of illustration,
FIG. 1 shows only a portion of the bronchial tree 120, which is described
in more detail below with reference to FIG. 4.

[0046] Throughout this description, certain terms are used that refer to
relative directions or locations along a path defined from an entryway
into the patient's body (e.g., the mouth or nose) to the patient's lungs.
The path of airflow into the lungs generally begins at the patient's
mouth or nose, travels through the trachea into one or more bronchial
passageways, and terminates at some point in the patient's lungs. For
example, FIG. 1 shows a path 102 that travels through the trachea 125 and
through a bronchial passageway into a location in the right lung 110. The
term "proximal direction" refers to the direction along such a path 102
that points toward the patient's mouth or nose and away from the
patient's lungs. In other words, the proximal direction is generally the
same as the expiration direction when the patient breathes. The arrow 104
in FIG. 1 points in the proximal or expiratory direction. The term
"distal direction" refers to the direction along such a path 102 that
points toward the patient's lung and away from the mouth or nose. The
distal direction is generally the same as the inhalation or inspiratory
direction when the patient breathes. The arrow 106 in FIG. 1 points in
the distal or inhalation direction.

[0047] The lungs include a right lung 110 and a left lung 115. The right
lung 110 includes lung regions comprised of three lobes, including a
right upper lobe 130, a right middle lobe 135, and a right lower lobe
140. The lobes 130, 135,140 are separated by two interlobar fissures,
including a right oblique fissure 126 and a right transverse fissure 128.
The right oblique fissure 126 separates the right lower lobe 140 from the
right upper lobe 130 and from the right middle lobe 135. The right
transverse fissure 128 separates the right upper lobe 130 from the right
middle lobe 135.

[0048] As shown in FIG. 1, the left lung 115 includes lung regions
comprised of two lobes, including the left upper lobe 150 and the left
lower lobe 155. An interlobar fissure comprised of a left oblique fissure
145 of the left lung 115 separates the left upper lobe 150 from the left
lower lobe 155. The lobes 130, 135, 140, 150, 155 are directly supplied
air via respective lobar bronchi, as described in detail below.

[0049] FIG. 2 is a lateral view of the right lung 110. The right lung 110
is subdivided into lung regions comprised of a plurality of
bronchopulmonary segments. Each bronchopulmonary segment is directly
supplied air by a corresponding segmental tertiary bronchus, as described
below. The bronchopulmonary segments of the right lung 110 include a
right apical segment 210, a right posterior segment 220, and a right
anterior segment 230, all of which are disposed in the right upper lobe
130. The right lung bronchopulmonary segments further include a right
lateral segment 240 and a right medial segment 250, which are disposed in
the right middle lobe 135. The right lower lobe 140 includes
bronchopulmonary segments comprised of a right superior segment 260, a
right medial basal segment (which cannot be seen from the lateral view
and is not shown in FIG. 2), a right anterior basal segment 280, a right
lateral basal segment 290, and a right posterior basal segment 295.

[0050] FIG. 3 shows a lateral view of the left lung 115, which is
subdivided into lung regions comprised of a plurality of bronchopulmonary
segments. The bronchopulmonary segments include a left apical segment
310, a left posterior segment 320, a left anterior segment 330, a left
superior segment 340, and a left inferior segment 350, which are disposed
in the left lung upper lobe 150. The lower lobe 155 of the left lung 115
includes bronchopulmonary segments comprised of a left superior segment
360, a left medial basal segment (which cannot be seen from the lateral
view and is not shown in FIG. 3), a left anterior basal segment 380, a
left lateral basal segment 390, and a left posterior basal segment 395.

[0051] FIG. 4 shows an anterior view of the trachea 125 and a portion of
the bronchial tree 120, which includes a network of bronchial
passageways, as described below. In the context of describing the lung,
the terms "pathway" and "lumen" are used interchangeably herein. The
trachea 125 divides at a lower end into two bronchial passageways
comprised of primary bronchi, including a right primary bronchus 410 that
provides direct air flow to the right lung 110, and a left primary
bronchus 415 that provides direct air flow to the left lung 115. Each
primary bronchus 410, 415 divides into a next generation of bronchial
passageways comprised of a plurality of lobar bronchi. The right primary
bronchus 410 divides into a right upper lobar bronchus 417, a right
middle lobar bronchus 420, and a right lower lobar bronchus 422. The left
primary bronchus 415 divides into a left upper lobar bronchus 425 and a
left lower lobar bronchus 430. Each lobar bronchus, 417, 420, 422, 425,
430 directly feeds fluid to a respective lung lobe, as indicated by the
respective names of the lobar bronchi. The lobar bronchi each divide into
yet another generation of bronchial passageways comprised of segmental
bronchi, which provide air flow to the bronchopulmonary segments
discussed above.

[0052] As is known to those skilled in the art, a bronchial passageway
defines an internal lumen through which fluid can flow to and from a
lung. The diameter of the internal lumen for a specific bronchial
passageway can vary based on the bronchial passageway's location in the
bronchial tree (such as whether the bronchial passageway is a lobar
bronchus or a segmental bronchus) and can also vary from patient to
patient. However, the internal diameter of a bronchial passageway is
generally in the range of 3 millimeters (mm) to 10 mm, although the
internal diameter of a bronchial passageway can be outside of this range.
For example, a bronchial passageway can have an internal diameter of well
below 1 mm at locations deep within the lung.

Direct and Collateral Flow

[0053] Throughout this disclosure, reference is made to a "direct pathway"
to a targeted lung region and to a "collateral pathway" to a targeted
lung region. The term "direct pathway" refers to a bronchial passageway
that branches directly or indirectly from the trachea and either (1)
terminates in the targeted lung region to thereby directly provide air to
the targeted lung region; or (2) branches into at least one other
bronchial passageway that terminates in the targeted lung region to
thereby directly provide air to the targeted lung region. The term
"collateral pathway" refers to any pathway that provides air to the
targeted lung region and that is not a direct pathway. The term "direct"
is used to refer to air flow that flows into or out of a targeted lung
region via a direct pathway. Likewise, the term "collateral" is used to
refer to fluid flow (such as air flow) that flows into or out of a
targeted lung region via a collateral pathway. Thus, for example,
"direct" flow is fluid flow (such as air flow) that enters or exits the
targeted lung region via a direct pathway, and "collateral" flow is fluid
flow (such as air flow) that enters or exits the targeted lung region via
a collateral pathway.

[0054] A collateral flow can be, for example, air flow that flows between
segments of a lung, which is referred to as intralobar flow, or it can
be, for example, air flow that flows between lobes of a lung, which is
referred to as interlobar flow. One exemplary process of identifying a
collateral pathway that provides collateral air flow into a targeted lung
region is described below.

[0055] In accordance with one aspect of the disclosed methods, a targeted
region of the lung is identified, wherein the targeted lung region can
comprise, for example, a single one of the lung regions described above
with reference to FIGS. 1-3, or the targeted lung region can comprise a
collection of the regions described above. Alternately, the targeted lung
region can be some other portion of the lung. The targeted lung region
can be, for example, a diseased lung region for which it is desired to
bronchially isolate the region for the purposes of inhibiting fluid flow
into the region. As used herein, to "bronchially isolate" a lung region
means to modify the flow to the targeted lung region, such as to
regulate, prevent, or inhibit direct air flow to the lung region. In one
embodiment, after the targeted lung region is identified, an attempt is
made to bronchially isolate the targeted lung region, such as by
occluding the bronchial pathway(s) that directly feed air to the targeted
lung region. This may be accomplished, for example, by advancing and
implanting a bronchial isolation device into the one or more bronchial
pathways that directly feed air to the targeted lung region to thereby
regulate direct flow into the lung region.

[0056] The bronchial isolation device can be, for example, a device that
regulates the flow of air into a lung region through a bronchial
passageway. Some exemplary bronchial isolation devices comprised of flow
control elements are described in detail below with reference to FIG.
19-25. In addition, the following references describe exemplary flow
control elements: U.S. Pat. No. 5,594,766 entitled "Body Fluid Flow
Control Device; U.S. patent application Ser. No. 09/797,910, entitled
"Methods and Devices for Use in Performing Pulmonary Procedures"; and
U.S. patent application Ser. No. 10/270,792, entitled "Bronchial Flow
Control Devices and Methods of Use". The foregoing references are all
incorporated herein by reference in their entirety and are all assigned
to Emphasys Medical, Inc., the assignee of the instant application.

[0057] If the targeted lung region does not collapse, then it can be
assumed that the targeted lung region is not collapsing because of
collateral air flow into the lung. In such a case, it is desirable to
modify collateral flow into the targeted lung region in order to
encourage collapse or to achieve a desired flow dynamic for the lung
region. For example, the collateral flow into the targeted lung region
can be completely prevented so that there is no collateral flow into the
targeted lung region. Alternately, the collateral flow into the targeted
lung region can simply be reduced, such as to minimize the effect of the
collateral flow on the targeted lung region.

Use of Flowable Therapeutic Agents to Reduce or Prevent Collateral Flow

[0058] One way of impeding collateral fluid flow into the targeted lung
region is by injecting one or more flowable therapeutic agents into the
targeted lung region in order to partially or completely seal the
collateral pathway(s) that are providing collateral flow into the
targeted lung region. The agent is "flowable" in that the agent is at
least initially in a fluid state, which can be, for example, a liquid,
gas, aerosol, etc. The agent is "therapeutic" in that, when the agent
contacts lung tissue, the agent generates a reaction in the tissue of the
targeted lung region that serves to reduce, inhibit, or prevent
collateral fluid flow into the targeted lung region. The reaction can
result in, for example (1) gluing or sealing portions of the targeted
lung region together to thereby seal collateral pathways; (2) sclerosing
or scarring target lung tissue to thereby occlude the collateral
pathway(s) and seal off collateral flow into the targeted lung region;
(3) promoting fibrosis in or around the targeted lung region to thereby
seal off collateral flow into the region; (4) creating of an inflammatory
response that would seal or fuse collateral pathway(s) that lead into the
targeted lung region; (5) or creation of a bulking agent that fills space
(such as space within the targeted lung region and/or the collateral
pathway) and thereby partially or entirely seal off collateral flow into
the targeted lung region.

[0059] A variety of flowable therapeutic agents have been identified that
achieve one or more of the above reactions in lung tissue. The agents
include, for example, the following:

[0060] (1) a foam created from either synthetic materials or natural
biological materials that has one or more of the following-described
properties. According to one property, the foam expands in volume from an
initial injected volume to an expanded volume by a predetermined volume
amount. For example, the foam may double in volume from an injected
volume to expanded volume. Such volume expansion would cause the foam to
fill-up and seal the volume of the targeted lung region or the volume of
a collateral pathway. According to another property, the foam can be
resorbable or degradable in the tissue of a patient's body, such that,
when the foam is injected into the targeted lung region, the targeted
lung region would absorb the foam and shrink in volume. For example, the
foam could comprise a biodegradable polymer, such as polyethylene glycol
(PEG) or polyglycolic acid (PGA). In another example, the foam could be a
biodegradable polymer that is foamed with hydrogen or some other gas and
that is permeable through the cellular structure of the foam.

[0061] When a foam as described above is injected into the targeted lung
region, gas would begin to diffuse out of the foam matrix, which would
cause cells within the foam to collapse. As the foam collapses, the
adjacent tissue will be drawn to a smaller volume simultaneously due to
adhesion between the foam and the surrounding tissue. In one embodiment,
the foam has balanced properties of flow and viscosity in order to
increase the likelihood that the foam will adequately fill the targeted
lung region. Such balanced properties would also reduce the likelihood of
the foam running or leaking into regions of the lung adjacent to the
targeted lung region through the collateral pathway(s). The foam can
retain a foamy consistency until it is absorbed into the lung tissue, or
it can cure and harden and then dissolve over time.

[0062] (2) A sealant or glue, such as, for example, fibrin, fibrinogen and
thrombin epoxy, various cyanoacrylate adhesives and sealants, such as
n-butyl-2-cyanoacrylate, synthetic biocompatible sealants made from
polyethylene polymers, etc.

[0066] One example of an appropriate bulking material is the Onyx Liquid
Embolic System manufactured by Micro Therapeutics, Irvine, Calif. This
material is ethylene vinyl alcohol copolymer combined with micronized
tantalum powder for fluoroscopy contrast dissolved in dimethl sulfoxide
(DMSO) solvent. It solidifies through precipitation upon contact with an
aqueous solution, such as saline, and forms a spongy mass.

[0067] (6) Agents for inducing a localized infection and scar such as, for
example, a weak strain of Pneumococcus.

[0071] (10) Components of the extracellular matrix (ECM) such as
hyaluronic acid (HA), chondroitin sulfate (CS), fibronectin (Fn), or
ECM-like substances such as poly-L-lysine or peptides consisting of
praline and hydroxyproline.

[0072] Any well-known radiopaque contrast agent could be added to the
therapeutic agent in order to facilitate viewing of the agent as it is
dispersed in the targeted lung region. A sufficient quantity of agent is
dispersed to seal collateral pathways, but not so much that adjacent
tissue is affected. The flowable therapeutic agents that can be used to
limit collateral flow into a targeted lung region are not limited to
those described above.

Identification of Regions for Treatment

[0073] As discussed above, the targeted lung region can be an entire lobe
of one of the lungs 110, 115, or the targeted lung region can be one or
more lung segments, such as, for example, the lung segments described
above with reference to FIGS. 2 and 3. In the case of the targeted lung
region being a lung lobe, an attempt is made to bronchially isolate the
target lobe by sealing the direct pathways(s) into the target lobe, such
as by implanting a bronchial isolation device into the lobar bronchus
that supplies air to the targeted lobe. If the targeted lobe still does
not collapse, then it can be assumed that a collateral pathway is
supplying air to the targeted lobe, wherein the collateral pathway is
through an incomplete interlobar fissure. The outer surface of the lung
is covered with a serous membrane called the visceral pleura. When the
fissure between lobes is complete, the two adjacent lobes are separated
and are completely covered with visceral pleura of all surfaces, and
there is no collateral air flow possible between lobes. When the fissure
is incomplete, the adjacent lobes are not completely separated, the
visceral pleura does not completely surround the lobes, and parenchyma
from the adjacent lobes in the incomplete portion of the fissure touch
and are not separated. This incomplete formation of the fissure occurs
naturally in about 50% of fissures in human lungs, and collateral air
flow can occur between the lobes through these regions. See, Raasch B N,
et al. Radiographic Anatomy of the Interlobar Fissure: A Study of 100
Specimens. AJR 1982;138:1043-1049. When there is collateral airflow
through an incomplete interlobar fissure thereby preventing collapse of
the treated lobe, the lung can be treated to cause the fissure to seal
(either partially or entirely) and thereby reduce or prevent collateral
flow into the targeted lung lobe via the interlobar fissure.

[0074] FIG. 5 shows an example of a lung lobe that has been bronchially
isolated using a bronchial isolation device comprised of a flow control
element, which regulates fluid flow through a bronchial passageway that
supplies fluid to the lobe. The lobe receives collateral air flow through
a collateral pathway comprised of an incomplete interlobar fissure. As
shown in FIG. 5, a bronchial isolation device 510, such a flow control
element, is implanted in the right middle lobar bronchus 420 in order to
prevent direct flow into the targeted lung region comprised of the right
middle lobe 135. However, the right middle lobe 135 is still receiving
collateral flow (as exhibited by a series of arrows 512 in FIG. 5)
through a collateral pathway comprised of an incomplete right transverse
fissure 128. The collateral flow comes from the right upper lobar
bronchus 417 and passes into the right middle lobe 135 through the
incomplete right transverse fissure 128. Thus, the right upper lobar
bronchus 417 can also be considered to be a portion of the collateral
pathway into the right middle lobe 135. The collateral flow into the
right middle lobe 135 could be prevented or reduced by sealing the air
pathways through the incomplete right transverse fissure 128 where the
middle lobe 135 contacts the inferior surface of the right upper lobe
130.

[0075] In another exemplary scenario, the targeted lung region can be a
specific lung segment or some other portion of the lung that is within a
lobe. In this case, an attempt is made to bronchially isolate the
targeted lung segment (or other portion of the lung), such as by
inserting a flow control element into the direct pathway(s) to the
targeted lung segment. If the targeted lung segment still does not
collapse, it can be assumed that the flow is originating from other lung
segments or other regions within the same lobe as the targeted segment,
or from an incomplete interlobar fissure that is adjacent to the targeted
lung segment. FIG. 6 shows an example of this scenario. As shown in FIG.
6, a targeted lung segment 610 is located within the right upper lobe
130. The targeted lung segment 610 can receive direct flow via segmental
bronchus 615. The targeted lung segment 610 also receives collateral flow
from an adjacent segment 620 that is also located within the right upper
lobe 130.

[0076] In another example with reference to FIG. 6, a targeted lung
segment 630 is located in the right upper lobe 130 adjacent to the right
transverse fissure 128. The targeted lung segment 630 can receive
collateral flow from an adjacent lung segment in the right upper lobe
130. The targeted lung segment 130 can also receive collateral flow from
the right middle lobe 135 via an incomplete right transverse fissure 128,
in which case a bronchial passageway of the right middle lobe 135 is the
source of the collateral flow.

[0077] If collateral flow to a targeted lung segment is originating from
other segments or regions within the same lobe as the targeted lung
region, or is originating from a separate, adjacent lobe via an
incomplete fissure, it might be necessary to determine the bronchial
passageway that is supplying collateral flow to the targeted lung region.
One method of determining the magnitude of collateral flow, using
selective bronchial balloon catheterization combined with ventilation on
a helium-based marker gas and a helium detector, is disclosed in the
literature. See, Morrell N W, et al. Collateral Ventilation and Gas
Exchange in Emphysema, Am J Respir Crit Care Med 1994;150:635-41.

[0078] One technique of identifying the bronchial passageway(s) that feed
the parenchyma that communicates through the incomplete interlobar
fissure with the targeted lung portion is now described. According to
this technique, the bronchial sub-branches, such as segmental bronchi,
feeding parenchyma adjacent to the interlobar fissure of an isolated lobe
are determined fluoroscopically utilizing a standard guide wire. The
following example illustrates the technique as applied in the right upper
lobe, although the same principles could be used in any of the human
lung's five lobes or any segments within those lobes. Although the lung
is 3-dimensional and the airways are not sequentially related to linear
lung regions (e.g., the most inferior segmental bronchus may partially
feed the mid-section of a lung lobe or may preferentially feed the
anterior or posterior aspect of that lobe), the goal is to determine the
lowest (most inferior) sub-branch of the target upper lobe, as this
sub-branch provides airflow to the lung parenchyma that borders the
fissure between the upper lobe and the middle and lower lobes.

[0079] In a first step of the technique, a bronchoscope is passed through
the most inferior bronchus as seen from a bronchoscopic perspective. This
is performed according to well-known methods using a standard
bronchoscope. A guidewire is then passed through the working channel of
the bronchoscope and visually fed into the subsequent, most inferior
sub-branches to the visual limits of the bronchoscope. The guidewire is
then advanced further with the aid of fluoroscopic visualization. For
inferior/superior determination, the fluoroscope will generally be in an
anterior-posterior orientation (90 degrees to the patient's chest). The
position of the guidewire relative to fluoroscopic landmarks (e.g.:
relative to a rib or to the diaphragm) is then noted. The aforementioned
steps are repeated in multiple sub-branches until it can be determined
which bronchial sub-branch feeds the most inferior lung tissue (and thus
adjacent to the interlobar fissure), and this sub-branch is selected for
treatment.

[0080] Utilizing a fully articulating C-arm (fluoroscope), these steps can
be repeated in other views (e.g. the camera in a 90 degree lateral view
for anterior/posterior position) to map the sub-branches in 3-dimensions.
In this way, a physician can determine which bronchial sub-branch or
branches feed the most inferior lung tissue, tissue that borders the
right middle and right lower lobes. This technique could be applied to
any lobe in the lung, and to either the inferior or superior surfaces.

Delivery of Flowable Therapeutic Agent to Targeted Lung Region

[0081] The flowable therapeutic agent can be delivered to the targeted
lung region according to a variety of methods. Some exemplary methods of
delivering a flowable therapeutic agent to the targeted lung region are
described below. Regardless of the method used, the therapeutic agent can
be delivered to the targeted lung region either before or after an
attempt is made to bronchially isolate the targeted lung region using a
bronchial isolation device, or without bronchial isolation.

[0082] FIG. 7 illustrates an example of a method wherein a flowable
therapeutic agent 705 is delivered to a targeted lung region using a
delivery catheter 710. The targeted lung region is located in the right
middle lobe 135 of the right lung 110. The delivery catheter 710 can be a
conventional delivery catheter of the type known to those of skill in the
art. The delivery catheter 710 is deployed in a bronchial passageway,
such as in the segmental bronchi 715, that leads to the targeted lung
region. The delivery catheter 710 is deployed such that a distal end of
the catheter 710 is positioned distal of a bronchial isolation device 510
that has also been deployed in the bronchial passageway 710. As
mentioned, the bronchial isolation device 510 can be deployed either
before or after deployment of the delivery catheter 710.

[0083] Once the delivery catheter 710 is deployed in the targeted lung
region, the flowable therapeutic agent 705 can be delivered into the
targeted lung region using the delivery catheter 710. This can be
accomplished by passing the flowable therapeutic agent through an
internal lumen in the delivery catheter so that the agent exits a hole in
the distal end of the delivery catheter 710 into the targeted lung
region. As shown in FIG. 7, the distal end of the delivery catheter 710
can be sealed within the targeted lung region by inflating a balloon 720
that is disposed near the distal end of the catheter according to
well-known methods. In another embodiment, shown in FIG. 8, the bronchial
isolation device 510 provides the sealing so that a balloon is not needed
when delivering the flowable therapeutic agent 705 using the delivery
catheter 710.

[0084] FIG. 9 illustrates another method of delivering the flowable
therapeutic agent to the targeted lung region. According to the method
shown in FIG. 9, a delivery device, such as a delivery catheter or a
hypodermic needle 910, is used to percutaneously inject the flowable
therapeutic agent 705 directly into the lung tissue of the targeted lung
region. The hypodermic needle 910 is used to puncture the chest wall
according to well-known methods so that a sharpened delivery tip 915 of
the needle 910 locates within the targeted lung region. For example, the
targeted lung region could comprise a portion of the right middle lobe
135 located near the fissure 128, as shown in FIG. 9. The hypodermic
needle 910 is then used to puncture the chest wall and the needle 910 is
positioned so that the delivery tip 915 locates within the right middle
lobe 135. The flowable therapeutic agent 705 is then injected directly
into the targeted lung region via the hypodermic needle 910 according to
well-known methods.

[0085] FIG. 10 shows yet another method of delivering the flowable
therapeutic agent to the targeted lung region. According to this method,
a delivery catheter 710 has a distal tip 1005 that can be used to
puncture the wall of a bronchial passageway 1010 at a location that is at
or near the targeted lung region. The distal tip 1005 is configured to
facilitate puncturing of the bronchial wall, as described more fully
below. Once the distal tip 1005 has been used to puncture the bronchial
wall, the distal tip of the delivery catheter 710 is passed through the
bronchial wall and the flowable therapeutic agent can be injected into
the targeted lung region through the delivery catheter 710. The method
shown in FIG. 10 differs from the method described above with reference
to FIGS. 7 and 8 in that the method shown in FIG. 10 actually punctures
the bronchial wall so that the flowable therapeutic agent can be injected
directly into the lung tissue. The method shown in FIGS. 7 and 8 does not
include puncturing of the bronchial wall, and the flowable therapeutic
agent is injected into the bronchial lumen leading to the targeted lung
region rather than directly into the lung tissue.

[0086] The puncturing of the bronchial wall can be accomplished using any
of a variety of methods and devices. According to one embodiment, the
distal tip 1010 of the delivery catheter is configured to facilitate
puncturing of the bronchial wall. For example, the distal tip 1005 can be
sharpened to an appropriate sharpness that will facilitate puncturing of
a bronchial wall. It has been determined that a delivery catheter with a
diameter of up to 3 millimeters (mm) will be sufficient. Alternately, a
hypodermic needle can be mounted on the distal tip 1005 to facilitate
puncturing of the bronchial wall. In another configuration, a stiff
guidewire is delivered to the targeted lung region via the inner lumen of
a flexible bronchoscope. The guidewire is then used to puncture the
bronchial wall. After puncturing, a delivery catheter is delivered over
the stiff guidewire to the targeted lung region. In another configuration
radio frequency (RF) energy is applied to a catheter that comprises an RF
cutting tip, and the cutting tip is applied to the bronchial wall at a
location at or near the targeted lung region, thereby causing the
bronchial wall to puncture. A device approved for this purpose is the
Exhale RF Probe, Broncus Technologies, Inc. Mountain View, Calif., FDA
510(k) #K011267. In yet another configuration, a flexible biopsy forceps
is delivered through a working channel of the bronchoscope and used to
cut a hole through the bronchial wall in a well-known manner.

[0087] The delivery catheter 710 can be deployed at the targeted lung
region according to a variety of methods. For example, with reference to
FIG. 11, the delivery catheter 710 can be deployed using a bronchoscope
1111, which in an exemplary embodiment has a steering mechanism 1115, a
delivery shaft 1120, a working channel entry port 1125, and a
visualization eyepiece 1130. The bronchoscope 1111 has been passed into a
patient's trachea 125 and guided into the right primary bronchus 410
according to well-known methods. The delivery catheter 710 is then
deployed into the working channel entry port 1125 and down a working
channel (not shown) of the bronchoscope shaft 1120, and the distal end
1135 of the catheter 710 is guided to a desired location within the
bronchial tree, such as to a lobar bronchi 417 located within the upper
lobe 130 of the right lung 110. The steering mechanism 11 15 can be used
to deliver the shaft 1120 to a desired location.

[0088] Alternately, the delivery catheter 710 can have a central guidewire
lumen and can be deployed using a guide wire that guides the catheter to
the delivery site. The delivery catheter 710 could have a well-known
steering function, which would allow the catheter 710 to be delivered
with or without use of a guidewire.

[0089] In yet another method of delivering the flowable therapeutic agent,
one or more nasal cannulae are deployed through a patient's nasal cavity,
through the trachea, and to a desired location in the bronchial tree 120
at the targeted lung region. One or more bronchial isolation devices,
such as a flow control element, can also be deployed to bronchially
isolate the targeted lung region, with a distal end(s) of the cannula(e)
being passed through the bronchial isolation device(s). Alternately, a
catheter with multiple divided lumens or cannulae could be deployed. The
cannula can be left in place for a desired amount of time and an infusion
of one or more flowable therapeutic agents is deployed to the targeted
lung region via the cannula. The flowable therapeutic agents could be
continuously or intermittently administered at a desired flow rate until
the desired level of therapeutic effect has been obtained. In another
embodiment, the delivery catheter 710 can be used to bronchially isolate
the targeted lung region without the use of, or in combination with the
use of, a flow control element. In such a case, the distal end of the
delivery catheter 710 is equipped with a balloon (such as the balloon 720
shown in FIG. 7), which is inflated to occlude or partially occlude the
bronchial passageway that provides fluid flow to the targeted lung
region. In this manner, fluid flow through the bronchial passageway can
be reduced or eliminated.

Controlling Dispersion of the Therapeutic Agent in the Lung

[0090] In the course of delivering the therapeutic agent to the targeted
lung region, it can be desirable to control the dispersion of the
therapeutic agent in the lung so that the agent does not flow through any
collateral pathways into areas of healthy lung tissue. It can also be
desirable to move the therapeutic agent preferentially toward the
collateral pathway(s) (rather than toward some other area of the lung) in
order to increase the likelihood that sealing of collateral pathway(s) is
successful.

[0091] One way of controlling the movement of the therapeutic agent within
the lung is to provide pressure differentials in different regions of the
lung, wherein the pressure differentials encourage the therapeutic agent
to flow in a desired manner. For example, as shown in FIG. 12, a targeted
lung region 1210 is located in the right lower lobe 140 of the right lung
110. A healthy lung region 1220 is located adjacent to the targeted lung
region 1210. The pressure within the targeted lung region is P1 and the
pressure within the adjacent lung region 1220 is P2. If P1 is greater
than P2, then a therapeutic agent located in the targeted lung region
1210 will be inclined to flow toward the adjacent lung region 1220 due to
the pressure differential. Likewise, if P2 is greater P1, then a
therapeutic agent located in the targeted lung region 1210 will be
inclined to flow away from the adjacent lung region 1220.

[0092] One way to accomplish such a pressure differential is to control
the injection pressure that is used to inject the therapeutic agent into
the targeted lung region, and to also control a back pressure in an
adjacent lung region where collateral pathways to the targeted lung
region originate. If the therapeutic agent is radiopaque, a physician can
view the extent of the therapeutic agent dispersion while also varying
the injection pressure and the back pressure to control the dispersion.

[0093] This is described in more detail with reference to FIG. 13, which
shows a cross-sectional view of the right lung 110, wherein the targeted
lung region comprises the right middle lobe 135, which is adjacent to a
healthier lung region comprised of the right upper lobe 130. The
incomplete right transverse fissure 128 provides a collateral pathway
through which collateral flow originating in the right upper lobe 130
passes into the right middle lobe 135. A first delivery catheter 710,
which can have a balloon 720, is passed through a bronchial isolation
device 510 so that the distal end of the catheter 710 is disposed in the
targeted lung region. A second catheter 1305 is deployed in a bronchial
passageway that provides flow to a lung region adjacent to the target
region, wherein some collateral flow originates at the adjacent lung
region. For example, FIG. 13 shows the second catheter 1305 deployed
through the right lobar bronchus 417, which provides flow to the right
upper lobe 130 where the collateral flow into the right middle lobe
originates. The second catheter can have a balloon 1310 that is inflated.

[0094] The delivery catheter 710 is then used to inject the flowable
therapeutic agent 705 into the targeted lung region at a desired
injection pressure. This will cause the targeted lung region to achieve a
pressure P1. While the therapeutic agent is being injected, a suction can
be applied to the distal end of the second catheter 1305 to thereby
achieve a pressure P2 in the adjacent lung region comprised of the right
upper lobe 130. By controlling the injection pressure and suction, a
desired pressure differential between P1 and P2 can be achieved to
thereby control the dispersion of the therapeutic agent. The pressure
differential can be manipulated to encourage the therapeutic agent to
flow toward the collateral pathway and even enter the collateral pathway.
As discussed, the dispersion can be visually monitored if the therapeutic
agent includes a radiopaque.

[0095] When the desired dispersion level has been achieved, such as when
the therapeutic agent has filled the targeted lung region or has filled
the collateral pathways, it might then be desirable to further control
the dispersion to reduce the likelihood that the therapeutic agent will
flow into the healthy lung region. This can be accomplished by again
varying the pressure differential so that the therapeutic agent no longer
flows towards the healthy lung region. For example, the injection
pressure can be reduced or eliminated, while also changing the suction
pressure at the second catheter 1305. Suction can then be applied to the
delivery catheter 710 to remove any excess therapeutic agent from the
targeted lung region. The catheters 710,1305 are then removed. In this
manner, the therapeutic agent is preferentially moved toward the
collateral pathway(s).

[0096] The aforementioned technique for sealing the collateral flow
pathway could also be performed prior to the implantation of the
bronchial isolation device(s) 510.

Follow-On Therapy After Treatment with Flowable Therapeutic Agent

[0097] After the infusion of the flowable therapeutic agents into the
targeted lung region, a follow-on therapy procedure can be followed.
According to one procedure, the treated portion of the lung (the portion
of the lung to which the therapeutic agent was applied) is left alone,
with the therapeutic agent in place. The treated lung portion is allowed
to collapse by either absorption of the therapeutic agent by the body,
absorption of the trapped gas in the isolated lung region, exhalation of
trapped gas out through a flow control device (such as an implanted
one-way or two-way valve device) or any combination of these events.

[0098] According to another follow-on therapy procedure, the therapeutic
agent is removed from the lung following the passage of a predetermined
treatment period. The therapeutic agent could be removed after a short
period of time such as one or two minutes, or a longer period of 30 or 60
minutes. Alternatively, if required, the therapeutic agent could be
removed in a separate procedure hours or days later. The necessary time
period would depend on the particular therapeutic agent used. This could
be done with the implanted bronchial isolation devices in place, or could
be done before implantation of the bronchial isolation devices if the
therapeutic agent was deployed prior to implantation of the bronchial
isolation devices. The therapeutic agent can be removed from the lung in
any number of ways, which include the following: [0099] (a) Inflating
a balloon catheter in the bronchial passageway leading to the targeted
lung region and aspirating through the catheter central lumen. If
bronchial isolation devices had been implanted already, the suction in
the catheter would pull the excess therapeutic agent through the one-way
or two-way valves of the isolation devices. This method is likely not
used where the implanted devices are plugs or occluders. [0100] (b)
Crossing the implanted one-way or two-way valves with a catheter and
applying suction through the central lumen of the catheter. The catheter
could either be sealed by the valve in the implanted device, or it could
be a balloon catheter where the balloon is inflated in the bronchial
passageway distal to the implanted device. [0101] (c) Percutaneously
suctioning the therapeutic agent directly out of the lung tissue, such as
by using a hypodermic needle. [0102] (d) Suctioning the therapeutic
agent out of the targeted lung region through the a hole created in the
bronchial wall. This can be done using a new catheter or using the same
catheter as was used to inject the agent.

[0103] Thus, there have been disclosed several basic approaches to
injecting a flowable therapeutic agent for preventing or reducing
collateral flow into a targeted lung region. Some examples of the basic
approaches are summarized as follows: [0104] (a) Implant one or more
bronchial isolation devices to isolate targeted lung region; inject a
flowable therapeutic agent into the targeted lung region distal to the
bronchial isolation devices; allow the lung region to collapse, such as,
for example, by absorption of the therapeutic agent by the body,
absorption of the trapped gas in the isolated lung portion, exhalation of
trapped gas out through the implanted one-way or two-way valve devices,
or any combination of these events. [0105] (b) Implant one or more
bronchial isolation devices; inject a flowable therapeutic agent into the
targeted lung region distal to devices;

[0106] wait a pre-determined treatment time period; remove the therapeutic
agent, such as, for example, by using suction, needle aspiration, etc.;
and

[0107] allow the lung region to collapse, such as, for example, by
absorption of the trapped gas in the isolated lung portion, exhalation of
trapped gas out through the implanted one-way or two-way valve devices,
or both. [0108] (c) Inject a flowable therapeutic agent into the
targeted lung region;

[0109] implant bronchial isolation devices; allow the targeted lung region
to collapse, such as, for example, by absorption of the therapeutic agent
by the body, absorption of the trapped gas in the isolated lung portion,
exhalation of trapped gas out through the implanted one-way or two-way
valve devices, or any combination of these events. [0110] (d) Inject a
flowable a therapeutic agent into parenchyma of the targeted lung region;
implant one or more bronchial isolation devices; wait a pre-determined
treatment time period; remove the therapeutic agent, such as, for
example, using suction, needle aspiration, etc.; and allow lung region to
collapse, such as, for example, by absorption of the trapped gas in the
isolated lung portion, exhalation of trapped gas out through the
implanted one-way or two-way valve devices, or both. [0111] (e) Inject a
flowable therapeutic agent into the targeted lung region; wait a
pre-determined treatment time period; remove therapeutic agent; implant
bronchial isolation devices; and allow the lung region to collapse.
[0112] (f) Temporarily isolate the targeted lung region; inject a
flowable therapeutic agent into the targeted lung region; wait a
pre-determined treatment time period; and remove therapeutic agent.
[0113] (g) Temporarily isolate the targeted lung region; and inject a
flowable therapeutic agent into the targeted lung region. Application of
Energy to Reduce or Prevent Collateral Flow

[0114] An alternate way of reducing or preventing collateral fluid flow
into the targeted lung region is to apply energy to the targeted lung
region, wherein the application of energy generates a reaction in the
tissue of the targeted lung region that serves to reduce or prevent
collateral fluid flow into the targeted lung region. The reaction can
result in, for example: (1) gluing or sealing portions of the lung
together to thereby partially or entirely seal collateral pathways; (2)
sclerosing or scarring target lung tissue to thereby partially or
entirely occlude the collateral pathway(s) and partially or entirely seal
off collateral flow into the targeted lung region; (3) promoting fibrosis
in or around the targeted lung region to thereby partially or entirely
seal off collateral flow into the region; (4) creating of an inflammatory
response that would partially or entirely seal or fuse collateral
pathway(s) that lead into the targeted lung region. A variety of energy
sources have been identified that can be used to apply energy to lung
tissue to achieve any of the aforementioned reactions. The types of
energy include Beta-emitting radiation, radio frequency energy, heat,
ultrasound, cryo-ablation, laser energy, and electrical energy. The
process of identifying the lung region for treatment can be the same as
that described above with reference to the use of the flowable
therapeutic agent.

[0115] A variety of different methods can be used to deliver energy to a
desired location in the targeted lung region. Regardless of the method
used, the therapeutic agent can be delivered to the targeted lung region
either without bronchial isolation, or before or after an attempt is made
to bronchially isolate the targeted lung region using a bronchial
isolation device.

[0116] FIG. 14 illustrates a method wherein an energy source is delivered
to a targeted lung region using a delivery catheter 710. The targeted
lung region is located in the right middle lobe 135 of the right lung
110. The delivery catheter 710 can be a conventional delivery catheter of
the type known to those of skill in the art. The delivery catheter 710 is
deployed in a bronchial passageway, such as in the sub-segmental bronchi
715, that leads to the targeted lung region. A distal end of the catheter
710 is inserted into the bronchial passageway and is positioned distal of
a bronchial isolation device 510 that has been deployed in a bronchial
passageway that provides direct flow to the targeted lung region. As
discussed above, the bronchial isolation device 510 can be deployed
either before or after deployment of the delivery catheter 710.

[0117] Once the delivery catheter 710 is deployed in the targeted lung
region, an energy source 1410 can be delivered into the targeted lung
region using the delivery catheter 710. This can be accomplished, for
example, by passing a push wire 1415 having a distally-mounted energy
source 1410 through an internal lumen in the delivery catheter 710 so
that the energy source 1410 exits a hole in the distal end of the
delivery catheter 710 into the targeted lung region. Alternately, the
energy source 1410 can be mounted on the distal end of the delivery
catheter 710. The distal end of the delivery catheter 710 can be sealed
within the targeted lung region by inflating a balloon that is disposed
near the distal end of the catheter according to well-known methods.
Alternately, the bronchial isolation device 510 can provide the sealing
so that a balloon is not needed.

[0118] According to another method of delivering the energy, a delivery
device, such as delivery catheter or a hypodermic needle, is used to
percutaneously reach the targeted lung region by puncturing the chest
wall and outer surface of the lung. The energy source is then advanced
directly into the lung tissue. This would be similar to the method shown
in FIG. 9, although an energy source would be used in place of the
flowable therapeutic agent.

[0119] In yet another method of delivering the energy to the targeted lung
region, a delivery catheter has a distal tip that can be used to puncture
the wall of a bronchial passageway that is located at or near the
targeted lung region. The distal tip is configured to facilitate
puncturing of the bronchial wall. Once the distal tip's-has been used to
puncture the bronchial wall, the energy source is advanced into the
targeted lung region through the delivery catheter. This would be similar
to the process shown in FIG. 10. The puncturing of the bronchial wall can
be accomplished using any of a variety of methods and devices, such as
was described above with reference to FIG. 10.

[0120] The delivery catheter for delivering the energy source to the
targeted lung region could be deployed in the same manner described above
with reference to the flowable therapeutic agents, such as by using a
bronchoscope.

Exemplary Method for Applying Energy to Targeted Lung Region

[0121] The delivery of beta-emitting radiation could be accomplished with
a brachytherapy delivery system that includes a beta-emitting radiation
source mounted to the end of a delivery catheter, such as was described
above. As mentioned previously, this could be done either before or after
the implantation of bronchial isolation devices.

[0122] According to one method of applying the energy, a beta
radiation-emitting source is passed through one or more target bronchial
passageways, either sequentially or concurrently, that lead to the
targeted lung region. The source can also be passed through one or more
of the bronchial isolation devices that were previously implanted. The
radiation source is left in place for a period of time so as to elicit a
scarring/healing response in the treated lung tissue. For example, it may
be discovered through animal and/or human clinical trials that an
exposure time period of 30 minutes to one hour will achieve satisfactory
results. A maximum time may be identified wherein the risk of radiation
to the surrounding tissue is greater than the benefits of scarring the
target tissue. For example, it may be discovered that the radiation
source can remain in up to an hour, but that exposure for greater than 90
minutes increases risk to the patient.

[0123] In another application method, the application procedure is
performed over a predetermined time period and/or over bronchial
sub-branches. For example, a patient can first be admitted for a
procedure to deploy bronchial isolation devices, such as flow limiting
valves, and then discharged with periodic reassessment of anatomical or
clinical results. The physician and patient could decide when the next
step of transvalvular brachytherapy should take place (e.g.: 15-30 days
after the primary procedure). Brachytherapy could also be staged over
time in such a way as to minimize risk while continually assessing
benefit (e.g.: valves placed day one, first brachytherapy procedure of 30
minutes exposure day 30, second brachytherapy procedure of 30 minutes at
day 60, etc.). The first brachytherapy session could be targeted at the
RUL, inferior sub-segment of the anterior, segmental bronchus; the second
session would target the RUL superior sub-segment of the anterior,
segmental bronchus; etc.

[0124] The same procedures described above for beta-emitting radiation
could be followed for other radiation sources such as RF energy, heat,
ultrasound, or cryo-ablation. These energy sources might require
different treatment times, a different number of treatment sites, etc.,
but the general application method would be the same.

Use of Flow-Limiting Isolation Devices to Limit Collateral Flow

[0125] Another way of impeding collateral fluid flow into the targeted
lung region is now described, wherein flow-limiting devices are implanted
in the bronchial passageway leading to lung regions adjacent to the
target region, wherein the adjacent lung region that is not targeted for
collapse.

[0126] As with the previously described methods, the lung region targeted
for isolation and collapse is identified, and bronchial isolation devices
are implanted in all airways that provide direct flow to the targeted
lung region. The implanted isolation devices can be, for example, one-way
valves that allow flow in the exhalation direction only, one-way valves
that allow flow in the inhalation direction only, occluders or plugs that
prevent flow in either direction, or two-way valves that control flow in
both directions according to well-known methods. If the lung region does
not collapse, such as due to either absorption atelectasis, or through
exhalation of trapped gas through the implanted devices, then the lung
region is likely being kept inflated through collateral in-flow through
collateral pathways from adjacent lung regions. If the collateral flow
from-the adjacent lung regions could be reduced substantially or
eliminated, the targeted lung region will likely collapse.

[0127] One way to reduce or substantially eliminate the collateral flow
from adjacent lung regions is to implant inhalation flow limiting two-way
valve devices in the bronchial passageways leading to adjacent lung
regions not targeted for collapse, wherein the adjacent lung regions act
as a source for collateral flow into the targeted lung region. Such
devices would allow free fluid flow in the exhalation direction for the
adjacent lung regions, but would limit the flow to a predetermined level
in the inhalation direction. As a result, flow into the adjacent lung
region would be limited, thereby limiting the flow of gas into the
targeted lung region through the collateral pathways from the adjacent
lung regions. The flow limitation is desirably sufficient to allow the
isolated lung region to collapse, but would not collapse the adjacent
lung regions. Once sufficient time had passed to allow the targeted lung
region to become chronically atelectatic, the flow limiting two-way valve
devices could be removed from the adjacent lung regions in order to
restore normal ventilation to the lung portion not targeted for collapse.

[0128] An example of this method is shown in FIG. 15, which shows a
targeted lung region comprised of the right upper lobe 130 that is
isolated by one-way bronchial isolation devices 510 that are implanted in
all bronchial passageways leading to the lobe 130. The devices 510 are
one-way valve devices that stop all flow in the inhalation direction to
thereby prevent direct flow into the lobe 130. A flow limiting two-way
valve bronchial isolation device 1510 is implanted in the bronchial
passageway in the right middle lobe 135 in the segment that lies just
below the interlobar fissure 128 adjacent to the lobe 130. The device
1510 allows free flow in the exhalation direction and a limited flow in
the inhalation direction. This limits the flow into the middle lobe 135,
in a manner determined by the back flow restriction of the two-way valve.
By limiting the flow into the middle lobe 135, the collateral flow into
the targeted upper lobe 130 that originates in the middle lobe 130 is
also limited. The flow limitation into the middle lobe 135 is sufficient
to allow the right upper lobe 130 to collapse, as the collateral flow
into the upper lobe 135 via the fissure 128 is insufficient to inflate
the upper lobe 130.

[0129] One exemplary embodiment of a flow limiting two-way valve 2500 is
shown in FIGS. 22-25. In this embodiment, the valve would behave as a
one-way valve in the forward or exhalation direction in that it would
allow free flow of fluid through the valve. However, the valve would also
allow a controlled rate of flow in the reverse or inhalation direction.
This could be achieved in a duckbill style valve by adding a small flow
channel 2510 through the lips 2512 of the valve, as shown in FIG. 25. The
reverse flow channel shown would allow fluid to flow in the inhalation
direction, and the rate of flow would be controlled by diameter and
length of the flow channel.

Use of Percutaneous Suction to Limit Collateral Flow

[0130] Another method for limiting collateral flow into a targeted lung
region is through the use of percutaneous suction. As discussed,
bronchial isolation devices may be implanted in any bronchial passageways
that provide direct flow to the targeted lung region. Percutaneous
suction is then applied to the targeted lung region for a time period
sufficient to adhere or fuse the lung tissue in the targeted lung region
in a collapsed state such that the targeted lung region will not
re-inflate through collateral pathways after the suction is stopped.

[0131] The percutaneous suction method is described in more detail with
reference to FIG. 16, which shows the targeted lung region being located
in the right upper lobe 130. An attempt is made to bronchially isolate
the targeted lung region by implanting one or more bronchial isolation
devices 705 in bronchial passageway that provide direct flow into the
targeted lung region. A suction catheter 1610 is percutaneously inserted
into the targeted lung region, such as by inserting the catheter 705
through the rib space in a well-known manner. The suction catheter 1610
includes an internal lumen and has a distal end 1615 on which are located
one or more suction holes 1620 that communicate with the internal lumen.
A suction force can be applied to a proximal end 1625 of the catheter
1610 to suck fluid into the internal lumen through the suction holes 1620
on the distal end 1615 of the catheter 1610. A fixation balloon 1630 is
mounted on the catheter 1610 a short distance from the distal end 1615 of
the catheter 1610. In one embodiment, the fixation balloon 1630 is
mounted approximately 2 centimeters from the distal end 1615. An
exemplary suction catheter that can be used is the 8-French Venography
Catheter, manufactured by The Cook Group, Inc., Bloomington, Ind.

[0132] As shown in FIG. 16, the suction catheter 1610 is percutaneously
inserted into the targeted lung region so that the suction holes 1620 in
the distal end 1615 are positioned within the targeted lung region. The
fixation balloon 1630 is positioned in the pleural space of the lung and
is then inflated to thereby fix the suction catheter 1610 in a fixed
position and to also seal the incision that was used to percutaneously
insert the catheter 1610. The suction catheter 1610 can be maneuvered
into the correct location using guidance assistance, such as computer
tomography (CT) or fluoroscopic guidance.

[0133] After the suction catheter 1610 has been properly positioned, a
suction force can be applied to the internal lumen of the catheter to
thereby cause a sucking force that draws fluid into the internal lumen
through the suction holes 1620. The suction force will draw air or other
fluid in the targeted lung region into the internal lumen through the
suction holes 1620, which will aspirate the targeted lung region into a
collapsed state. It has been determined that a suction force of
approximately 100-160 mmHg is sufficient to aspirate the targeted lung
region into a collapsed state. The suction force can be continuously
maintained for a time period sufficient to permanently collapse the lung
and reduce the likelihood of inflation through collateral pathways. In
one embodiment, the suction is continuously maintained for a minimum time
period of eight hours. In another embodiment, the suction is maintained
for a time period of one to eight days. The suction can be performed
while the patient is on bed rest, using a stationary vacuum source, or it
could be performed using a portable vacuum source in order to permit the
patient to ambulate.

[0134] After the suction time period has elapsed, a flowable therapeutic
agent (such as any of the agents described above) can optionally be
infused into the targeted lung region. This could be performed using the
suction catheter 1610, such as by infusing the agent through a separate
internal lumen located in the catheter 1610 or through the same lumen
that was used for suction. The therapeutic agent could be used to
increase the likelihood that the targeted lung region is properly sealed.
The fixation balloon 1630 is then deflated and the suction catheter 1610
is removed.

Use of Two-Part Adhesive to Limit Collateral Flow

[0135] According to another method of inhibiting collateral flow into a
targeted lung region, a two-part adhesive or glue is used to occlude a
collateral pathway to the targeted lung region. The adhesive can comprise
a two-part mixture that includes a first part and a second part, wherein
the first part and the second part collectively solidify when brought
into contact with each other. The two parts do not necessarily require
complete mixing in order for the solidification to occur. The
solidification can be triggered, for example, by a catalytic reaction
that occurs when the two parts contact one another. In one embodiment,
the two-part glue is a fibrin glue and the two parts of the glue are
thrombin and fibrinogen.

[0136] A method for deploying a two-part adhesive in order to seal a
collateral pathway is now described. The collateral pathway is located in
a lung region between two or more bronchial passageway, such as a first
bronchial passageway and a second bronchial passageway. For example, as
shown in FIG. 17, the collateral pathway can be an incomplete interlobar
128 fissure that is located between a first bronchial passageway 1710 and
a second bronchial passageway 1715. The bronchial passageway are not
necessarily in the same lobe. For example, in FIG. 17 the bronchial
passageway 1710 is in the right upper lobe 130 and the bronchial
passageway 1715 is in the right middle lobe 135, where the targeted lung
region is also located.

[0137] According to the method, the first part of the two-part adhesive is
injected into the first bronchial passageway and the second part of the
two-part adhesive is injected into the second bronchial passageway. The
injection pressure and flow rates of the first and second parts can be
controlled to encourage the first and second parts to flow to a common
location, wherein the common location coincides with the location of the
collateral flow path. That is, the first and second parts will contact
one another within the collateral flow path. As mentioned, the first and
second parts solidify when they contact one another. In this manner, the
first and second parts solidify within the collateral flow path and
thereby partially or entirely seal the collateral flow path.

[0138] An example of this is shown in FIG. 17, which shows a
balloon-tipped catheter 1712 that has been deployed in the second
bronchial passageway 1715, which supplies direct flow to the targeted
lung region. A bronchial isolation device 510 is deployed in a segmental
bronchus 1735 that is proximal to the second bronchial passageway 1715 in
order to bronchially isolate the targeted lung region. The catheter 1712
is sealed within the bronchial passageway 1715 by inflating a balloon
1720 mounted on the catheter 1712. A second balloon-tipped catheter 1725
is deployed in the first bronchial passageway 1710 and sealed by
inflating a balloon 1730. The first part 1728 of the two-part adhesive is
then injected into the bronchial passageway 1715 via the catheter 1712
and the second part 1732 of the two-part adhesive is injected into the
bronchial passageway 1710 via the catheter 1725. The first and second
parts are injected in such a manner that they flow into the lung and meet
at the collateral pathway comprised of the incomplete interlobar fissure
128. As a result of the contact between the first and second parts, they
solidify within the interlobar fissure and thereby partially or entirely
seal the interlobar fissure.

[0139] Once the adhesive has solidified, any remaining quantity of the
first and second parts can be suctioned out of the lung. Alternately, the
first and second parts could be absorbable by the body so that excess
material need not be removed. The aforementioned technique for sealing
the collateral flow pathway could also be performed prior to the
implantation of the bronchial isolation device(s) 510.

Implanted Shunt Tubes

[0140] One of the major challenges with emphysematic patients is that
certain bronchial passageways collapse during exhalation, thus leading to
reduced flow through these lumens. This often results in trapped gas in
certain regions of the lung that exhale air through the collapsed lumen.
This in turn can lead to hyperinflation of the lung region, as well as
compression of the healthy lung tissue that is adjacent to the lung
region. One way of treating the hyperinflated lung region is to implant
bronchial isolation devices, such as one-way or two-way valves, in the
bronchial passageway that lead to the lung region in order to promote
lung region collapse. However, the effectiveness of the bronchial
isolation devices can be limited due to the reduced air flow during
exhalation through the native bronchial passageways, especially if
collateral flow is present.

[0141] One method of counteracting this effect is to implant one or more
shunt tubes that are inserted through the bronchial passageways and into
the targeted lung region comprised of a damaged lung region. The shunt
tubes provide a clear flow path for exhaled air that is not be occluded
by the collapsed bronchial passageway. In order to collapse the targeted
lung region, one-way valves may be either mounted to a proximal end of
the shunt tubes, or implanted in the bronchial passageways at some
distance proximal to the proximal end of the tubes. These valves allow
exhaled air to escape in the exhalation direction through the valve or
valves, but do not allow inhaled air to return to the isolated targeted
lung region. In this way, the targeted lung region eventually collapses
after sufficient air had been exhaled. Alternatively, a self expanding
braided tube can be used to prop the collapsed airway open. This allows
side branches to continue to exhale air into the braided tube while
keeping the bronchi open.

[0142] FIG. 18 shows an example of how shunt tubes can be utilized. A
bronchial isolation device 510 is implanted in a bronchial passageway of
the right upper lobe 130. Two implanted shunt tubes 1810 and 1820 are
shown deployed in two lumens. The shunt tubes 1810, 1820 are located
distal to the implanted isolation device 510. The shunt tubes 1810, 1820
keep the airways open and provide a flow path through which exhaled air
can pass. The implanted shunt tubes 1810 and 1820 are shown in FIG. 18 as
being implanted just distally to the implanted bronchial isolation device
510. Alternatively, the shunt tubes may be implanted more distally, and a
greater quantity may be implanted. The shunt tubes may be anchored in the
bronchial lumen in a number of ways. In a first embodiment, the shunt
tube have spring resilience and expand when released from a smaller
constrained diameter to a larger diameter, thus gripping the bronchial
lumen wall. Alternately, the shunt tubes may comprise a deformable
retainer that is expanded to grip the bronchial lumen wall by inflating a
balloon placed inside the collapsed shunt tube. The shunt tubes may also
comprise a cylindrical structure that increases in diameter when its
temperature is raised to body temperature. The shunt tubes may also have
barbs, prongs or other features on the outside that assist in gripping
the bronchial lumen wall for retention.

Exemplary Bronchial Isolation Devices

[0143] As discussed above, a target lung region can be bronchially
isolated by advancing a bronchial isolation device into the one or more
bronchial pathways that directly feed air to the targeted lung region.
The bronchial isolation device can be a device that regulates the flow of
fluid into or out of a lung region through a bronchial passageway. FIG.
19 shows a cross-sectional view of an exemplary bronchial isolation
device comprised of a flow control element 1910. It should be appreciated
that the flow control element 1910 is merely an exemplary bronchial
isolation device and that other types of bronchial isolation devices for
regulating air flow can also be used. For example, the following
references describe exemplary bronchial isolation devices: U.S. Pat. No.
5,594,766 entitled "Body Fluid Flow Control Device; U.S. patent
application Ser. No. 09/797,910, entitled "Methods and Devices for Use in
Performing Pulmonary Procedures"; and U.S. patent application Ser. No.
10/270,792, entitled "Bronchial Flow Control Devices and Methods of Use".
The foregoing references are all incorporated by reference in their
entirety and are all assigned to Emphasys Medical, Inc., the assignee of
the instant application.

[0144] With reference to FIG. 19, the flow control element 1910 is in the
form of a valve with a valve member 1915 supported by a ring 1920. The
valve member 1915 is a duckbill-type valve and has two flaps defining an
opening 1925. The valve member 1915 is shown in a flow-preventing
orientation in FIG. 19 with the opening 1925 closed. The valve member
1915 is configured to allow free fluid flow in a first direction (along
arrow A) while controlling fluid flow in a second direction (along arrow
B). In the illustrated embodiment, fluid flow in the direction of arrow B
is controlled by being completely blocked by valve member 1915. The first
and second directions in which fluid flow is allowed and controlled,
respectively, can be opposite or substantially opposite each other, such
as is shown in FIG. 19. The valve member 1915 functions as a one-way
valve by completely blocking fluid flow in a certain direction. It should
be appreciated that the flow control element could be configured to block
or regulate flow along two-directions.

[0145] FIGS. 20 and 21 show another embodiment of an exemplary flow
control element, comprising flow control element 2000. The flow control
element 2000 includes a main body that defines an interior lumen 2010
through which fluid can flow along a flow path. The flow of fluid through
the interior lumen 2010 is controlled by a valve member 2012. The valve
member 2112 in FIGS. 20-21 is a one-way valve, although two-way valves
can also be used, depending on the type of flow regulation desired. FIGS.
22-25 show an exemplary two-way valve member 2500.

[0146] With reference again to FIGS. 20-21, the flow control element 2010
has a general outer shape and contour that permits the flow control
device 2010 to fit entirely within a body passageway, such as within a
bronchial passageway. The flow control member 2000 includes an outer seal
member 2015 that provides a seal with the internal walls of a body
passageway when the flow control device is implanted into the body
passageway. The seal member 2015 includes a series of radially-extending,
circular flanges 2020 that surround the outer circumference of the flow
control device 2000. The flow control device 2000 also includes an anchor
member 2018 that functions to anchor the flow control device 2000 within
a body passageway. It should be appreciated that other types of flow
control devices can also be used to bronchially isolate the targeted lung
region.

[0147] The flow control element can be implanted in the bronchial
passageway using a delivery catheter. According to this process, the flow
control element is mounted on a distal end of the delivery catheter. The
distal end of the delivery catheter is then deployed to the bronchial
passageway, such as by inserting the delivery catheter through the
patient's mouth or nose, through the trachea, and through the bronchial
tree to the desired location in the bronchial passageway. The delivery
catheter can be deployed, for example, using a guide wire or without a
guide wire. In one embodiment, a bronchoscope is deployed to the location
in the bronchial passageway where the flow control device will be
deployed. The delivery catheter with the flow control element is then
deployed to the bronchial passageway by inserting the delivery catheter
through a working channel of the bronchoscope such that the distal end of
the delivery catheter and the attached flow control element protrude from
the distal end of the working channel into the bronchial passageway. The
flow control element is then removed from the delivery catheter so that
the flow control elements is positioned within and retained in the
bronchial passageway. U.S. patent application Ser. No. 10/270,792,
entitled "Bronchial Flow Control Devices and Methods of Use" (which is
assigned to Emphasys Medical, Inc., the assignee of the instant
application) describes various methods and devices for implanting a flow
control element into a bronchial passageway.

[0148] Although embodiments of various methods and devices are described
herein in detail with reference to certain versions, it should be
appreciated that other versions, embodiments, methods of use, and
combinations thereof are also possible. Therefore the spirit and scope of
the appended claims should not be limited to the description of the
embodiments contained herein.